Greater than one third of all HIV infections and AIDS cases are related directly or indirectly to injection drug use [1, 2]. While it is clear that drug use itself plays an important role in the spread of HIV infection, the effects of the drugs on HIV disease progression are not fully understood and various epidemiologic, animal and in vitro studies have provided some conflicting results. In the studies proposed here, we plan to address these issues in the context of SIV infection of rhesus macaques (Macaca mulatta). In this project, we will investigate the role of opioid (morphine) treatment in modulating the progression of HIV/AIDS using the SIVmac251 infected Indian rhesus macaque model. We will further determine if morphine plays a role in promoting NeuroAIDS through increased CNS invasion of SIV infected and/or uninfected macrophages. The proposed studies are critical for our understanding of how opioid drug abuse and replacement therapy affects the course of HIV disease progression. The studies proposed here may lead to new approaches to HIV therapeutics based on the u-opioid receptor agonists or antagonists. The proposed studies will be carried out in the context of two Specific Aims. Specific Aim 1 will determine if opioid treatment modulates the course of HIV/SIV disease progression using an SIV infected Indian rhesus macaque model. Specific Aim 2 will determine the effect of opioids in promoting the development of neuroAIDS in the SIV infected Indian rhesus macaques. The experimental design in these studies should lead to definitive answers regarding the role of opiates drugs of abuse in altering the pathogenesis of HIV/SIV and in contributing to CNS disease. These studies may provide important insights regarding approaches to intervention and therapy in patients with HIV infection, particularly those who are opiate drug abusers.